Saturday, November 14, 2015

Drugs in Clinical Pipeline: ONO-4059

ONO-4059 is a highly potent, oral and selective Bruton’s tyrosine kinase (Btk) inhibitor with an IC50 of 2.2 nM in biochemical assay. The compound covalently binds to BTK, and reversibly blocks BCR signaling and B-cell proliferation and activation. In a selectivity assay, ONO-4059 shows a two-fold potency against TEC kinase (IC50 = 5.3 nM) but it is highly selective against Fyn (IC50 = 2200 nM), Lck (IC50 = 790 nM) and LynA (IC50 = 3500 nM) [1].

In December 2014, Gilead Sciences signed a contract to help expedite development of Ono Pharmaceutical’s Ono-4059 program. The firms plan to work together to develop and commercialize ONO-4059, an oral Bruton's tyrosine kinase (BTK) inhibitor for the treatment of B-cell malignancies and other diseases. Gilead will have exclusive rights to develop and commercialize ONO-4059 in all countries of the world outside of Japan, South Korea, Taiwan, China, and the Association of Southeast Asian Nations countries (ASEAN), where Ono retains development and commercialization rights. Gilead hopes to develop ONO-4059 as a monotherapy or in combination with approved and investigational agents, including combinations with kinase inhibitors in Gilead's portfolio.

The activity of ONO-4059 is as follows:

IC50 (BTK enzyme assay) = 2.2 nM
IC50 (TEC enzyme assay) = 5.3 nM
IC50 (FYN enzyme assay) = 2200 nM
IC50 (LCK enzyme assay) = 790 nM

IC50 (LYNA enzyme assay) = 3500 nM

What's the structure of ONO-4059?

Till date, Ono pharma or Gilead pharma has not revealed the structure for ONO-4059. One of the patent publication in 2015 [3] provides some clues to ONO-4059. The biochemical assays correlates with those reported earlier [1, 2]. The IC50 value for BTK is 0.0021 uM, with 375-fold selectivity against LCK, 1057-fold against FYN and 1662-fold against LYNA.

The stereo-chemistry is a beta position. Interestingly, the base molecule has IC50 value for BTK as 0.007 uM, with 114-fold selectivity against LCK, 762-fold against FYN and 471-fold against LYNA [4].

Common Name: ONO-4059
Synonyms: ONO-4059; ONO 4059; ONO4059; GS 4059; GS-4059; GS4059; ONO-WG-307
CAS Number: 
Mechanism of Action: Kinase Inhibitor; BTK Inhibitor; Bruton’s Tyrosine Kinase Inhibitor
Indication: Various Cancers; Anti-inflammatory Agents
Development Stage: Phase I/II

Company: Ono Pharmaceutical\Gilead Pharma


1. Hendriks, R. W.; et. al. Targeting Bruton's tyrosine kinase in B cell malignancies. Nat Rev Cancer 2014, 14(4), 219-232.
2. Yoshizawa, T.; et. al. Development of a Bruton’s Tyrosine Kinase (Btk) inhibitor, ONO-4059: Efficacy in a Collagen Induced Arthritis (CIA) Model Indicates Potential Treatment for Rheumatoid Arthritis (RA). #1660, ACR, November 12, 2012. (here)
3. Yamamoto, S.; et. al. Purinone derivative hydrochloride. US20150274731A1
4. Yamamoto, S.; et. al. Purinone derivative. US20150094299A1